Cortistatin-14 Exerts Neuroprotective Effect Against Microglial Activation, Blood-brain Barrier Disruption, and Cognitive Impairment in Sepsis-associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a life-threatening deterioration of mental status in relation to long-term and disabling cognitive dysfunction that is common in intensive care units worldwide. Cortistatin-14 is a neuropeptide structurally resembling somastostatin, which has been proven to play a crucial role in sepsis. The present study aimed to explore the neuroprotective role of cortistatin-14 in sepsis-associated encephalopathy and its underlying mechanisms in a mouse model. A septic mice model was established using the cecal ligation and puncture (CLP) method. The novel object recognition test (NORT), open field test (OFT), elevated plus maze test (EPMT), and tail suspension test (TST) were used to explore the behavioral performance of the mice. Transmission electron microscopy was used to observe the microstructure of the blood-brain barrier (BBB). Evans Blue staining was used to examine the integrity of the BBB. Immunofluorescence was used to examine the morphology and infiltration of microglia. A multiplex cytokine bead array assay was used to determine cytokine and chemokine levels in mouse serum and brain tissues. NORT revealed that cortistatin treatment improved cognitive impairment in septic mice. OFT, EPMT, and TST indicated that cortistatin-14 relieved the anxiety-related behaviors of CLP mice. In addition, cortistatin-14 treatment decreased the levels of various inflammatory cytokines, including interleukin-1ß, interleukin-6, interferon-γ, and tumor necrosis factor-α in both the serum and brain of septic mice. Cortistatin reduced sepsis-induced blood-brain barrier disruption and inhibited microglial activation after the onset of sepsis. Cortistatin exerts neuroprotective effects against SAE and cognitive dysfunction in a CLP-induced mouse model of sepsis.

Overexpression of forkhead box M1 is associated poor survival in patients with nonsmall cell lung cancer.

AIMS: The association between forkhead box M1 (FOXM1) and survival of nonsmall cell lung cancer (NSCLC) has been extensively investigated. However, the results were conflicted and inconclusive. Therefore, we performed this meta-analysis to precisely estimate the association between FOXM1 and survival of NSCLC. MATERIALS AND METHODS: Studies were searched using the PubMed and EMBASE. The strength of the association was calculated with the hazard ratios (HRs) and respective 95% confidence intervals (CIs). RESULTS: Result of this meta-analysis showed that high expression of FOXM1 was significantly associated with shorter overall survival (OS) of NSCLC (HR = 1.82; 95% CI 1.45-2.29). In the stratified analysis by country, we found that the expression of FOXM1 was significantly associated with shorter OS in Chinese NSCLC patients (HR = 1.82; 95% CI 1.45-2.29). In addition, high expression of FOXM1 decreased the OS in patients with surgery (HR = 1.88; 95% CI 1.37-2.58). Furthermore, the results were still positive in both large sample size studies and small sample size studies. CONCLUSIONS: This meta-analysis showed that overexpression of FOXM1 might be associated with shorter OS of NSCLC patients.

Primary diffuse large B-cell lymphoma as a chest-wall mass: A case report.

RATIONALE: Primary diffuse large B-cell lymphoma of the chest wall is extremely rare. A majority of the pleural lymphomas develop in patients with chronic tuberculous pyothorax. The underlying mechanism might be attributed to the sustained stimulation of chronic inflammation. Surgery followed by adjuvant chemotherapy can improve the outcome in some patients with lymphoma localized only in the chest wall. Thus, an early diagnosis of pyothorax-associated lymphoma is essential as it is a malignant, life-threatening condition. PATIENT CONCERNS: A 79-year-old male complained of left-side chest pain for more than 2 months, which was not alleviated with nitrates and aspirin. The patient presented an intermittent low fever, anorexia, and marasmus, accompanied by tuberculosis 40 years ago and chronic left-side pyothorax. Also, ANCA (antineutrophil cytoplasmic autoantibody)-associated vasculitis occurred for >3years. DIAGNOSIS: Computed tomography scan showed a solid mass in the left lateral chest wall. The patient underwent ultrasonic-guided biopsy of the lesion. A diagnosis of primary diffuse large B-cell lymphoma of the chest wall was established after histological examination. INTERVENTION: Due to advanced age and poor physical condition, the patient received CHOP chemotherapy at a reduced dose. OUTCOMES: The patient died 5 days after the first cycle of chemotherapy with severe dyspnea and high fever. LESSONS: The chronic inflammation stimulation might result in the development of lymphoma in the chest wall of patients with long-term pyothorax, vasculitis, or other autoimmune diseases associated with malignancies. The fever, chest pain, or other nonspecific clinical symptoms in these patients should be under intensive focus as it might indicate the development of malignant lymphoma. Thus, histological examination in these patients is essential for accurate early diagnosis.

N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial.

Oxidative stress is considered to be part of the pathogenic mechanism for community-acquired pneumonia (CAP) and is closely linked to inflammation. Attenuation of oxidative stress would be expected to reduce pulmonary damage. Antioxidants have been found to be effective in alleviating lung injury and protecting against damage of other organs.The aim of the study was to compare the effect of adding N-acetylcysteine (NAC) to conventional treatment versus conventional treatment on oxidative stress, inflammatory factors, and radiological changes in CAP patients.Eligible CAP patients at Weihai Municipal Hospital were stratified and randomly assigned to either NAC group or non-NAC group between August 2016 and March 2017. The NAC group received conventional treatment for pneumonia and NAC (1200 mg/d). Thenon-NAC group received conventional therapy. malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAOC), tumor necrosis factor-α (TNF-α), and computed tomography (CT) images were evaluated at baseline and after treatment. The primary endpoint indicators were the changes in oxidative stress parameters (MDA, TAOC, SOD) and TNF-α after treatment in the NAC group compared with those in the non-NAC group. The secondary endpoint indicator was any difference in CT scores after treatment in the NAC group compared with the non-NAC group.Baseline levels of MDA, TAOC, SOD, and TNF-α were similar between the 2 groups before treatment. Plasma levels of MDA and TNF-α decreased more (P < .05 MDA:p 0.004, TNF-α:p <0.001) in the NAC group than the non-NAC group, and there was a reliable increase in TAOC content (p 0.005). There was no significant difference in increased plasma SOD activity between the groups (p 0.368), and the NAC group did not show a greater improvement from CT scores. No NAC-related adverse effects were observed.Addition of NAC therapy for CAP patients reduced MDA and TNF-α and increased TAOC. Treatment with NAC may help to reduce oxidative and inflammatory damage in pneumonia patients.

A study of community-acquired Mycoplasma pneumoniae in Yantai, China.

INTRODUCTION: Community-acquired pneumonia (CAP) is a global disease responsible for a large number of deaths, with significant economic impact. As diagnostic tools have increased in sensitivity, understanding of the etiology of CAP has begun to change. Mycoplasma pneumoniae is one of the major pathogens causing CAP. Macrolides and related antibiotics are first-line treatments for M. pneumoniae. Macrolide resistance has been spreading for 15 years and now occurs in worldwide. We undertook the first study on macrolide resistance of M. pneumoniae in Yantai. This may be helpful to determine the appropriate therapy for CAP in this population. OBJECTIVE: To investigate the rate and mechanism of macrolide resistance in Yantai. METHODS: Pharyngeal swab samples were collected from adult CAP patients. Samples were assayed by polymerase chain reaction (PCR) and cultivated to test for M. pneumoniae. Nested PCR was used to specifically amplify M. pneumoniae 23S rRNA gene fragments containing mutations, and amplicons were analyzed by CE-SSCP for macrolide resistance mutations. Results were confirmed by sequencing. Twenty-seven strains of M. pneumoniae were isolated and the activities of nine antibiotics against M. pneumoniae were tested in vitro. RESULTS: Out of 128 samples tested, 27 were positive for M. pneumoniae. Mycoplasma 100% macrolides resistance to Mycoplasma pneumoniae. The mechanism of macrolides resistance was A2063G point mutation in the sequence directly binding to macrolides in the 23S rRNA V domain in vitro. The mean pyretolytic time for the fluoroquinolone group was 4.7 ±2.9 d, which was significantly shorter than 8.2 ±4.1 d for the azithromycin group. CONCLUSIONS: Macrolides are not the first-line treatment for M. pneumoniae respiratory tract infections in Yantai.

INTRODUCCIÓN: Neumonía adquirida por en la comunidad (NAC) es una enfermedad responsable por un gran número de muertes y un impacto económico importante. Debido a que el diagnostico incrementó la sensibilidad, se cambió la etiología de la NAC. Adicionalmente, Mycoplasma pneumoniae es uno de los patógenos que causan la NAC. Los macrólidos y antibióticos relacionados son la primera línea de tratamiento para M. pneumoniae. La resistencia a macrólidos se aumentó en los últimos 15 años y ahora se encuentra distribuido en todo el mundo. Nosotros realizamos el primer estudio de resitencia a M. pneumoniae a los macrólidos en Yantai. Esto podría ser útil para determinar una terapia apropiada para NAC en esta población. OBJETIVO: Investigar la tasa y el mecanismo para la resitencia a los macrólidos en Yantai. MÉTODOS: Se colectaron muestras faringeas usando un hisopo. Las muestras se analizaron mediante la reacción en cadena de la polimerasa (PCR) y por cultivo para M. pneumoniae. Se uso una PCR anidad para amplificar fragmentos del gen 23S rRNA especifico con las mutaciones para M. pneumoniae. Se analizaron amplicomes por CE-SSCP para determinar la resitencia a los macrólidos. Estos resultados se confirmaron por secuenciación. Se aislaron 27 cepas de M. pneumoniae y se probaron nueve antibióticos in vitro. RESULTADOS: De 128 muestras, 27 fueron positivas para M. pneumoniae. Se determinó una resistencia a macrólidos por Mycoplasma del 100%. Los mecanismos de esta resitencia fue una mutacion punctual A2063G en la secuencia que se une directamente a los macrólidos en el dominio 23S rRNA V in vitro. El tiempo piotolítico medio para el grupo de fluoroquinolonas fue 4.7 ±2.9 d, que fue significativamente más corto que para el grupo de azitromicina: 8.2 ±4.1 d. CONCLUSIONES: Los macrólidos no son la primera linea de tratamiento para las infecciones del tracto respiratorio contra M. pneumoniae respiratory tract infections en Yantai.

A study of community-acquired Mycoplasma pneumoniae in Yantai, China / Estudio de Mycoplasma pneumoniae adquirido en la comunidad en Yantai, China

Abstract Introduction: Community-acquired pneumonia (CAP) is a global disease responsible for a large number of deaths, with significant economic impact. As diagnostic tools have increased in sensitivity, understanding of the etiology of CAP has begun to change. Mycoplasma pneumoniae is one of the major pathogens causing CAP. Macrolides and related antibiotics are first-line treatments for M. pneumoniae. Macrolide resistance has been spreading for 15 years and now occurs in worldwide. We undertook the first study on macrolide resistance of M. pneumoniae in Yantai. This may be helpful to determine the appropriate therapy for CAP in this population. Objective: To investigate the rate and mechanism of macrolide resistance in Yantai. Methods: Pharyngeal swab samples were collected from adult CAP patients. Samples were assayed by polymerase chain reaction (PCR) and cultivated to test for M. pneumoniae. Nested PCR was used to specifically amplify M. pneumoniae 23S rRNA gene fragments containing mutations, and amplicons were analyzed by CE-SSCP for macrolide resistance mutations. Results were confirmed by sequencing. Twenty-seven strains of M. pneumoniae were isolated and the activities of nine antibiotics against M. pneumoniae were tested in vitro. Results: Out of 128 samples tested, 27 were positive for M. pneumoniae. Mycoplasma 100% macrolides resistance to Mycoplasma pneumoniae. The mechanism of macrolides resistance was A2063G point mutation in the sequence directly binding to macrolides in the 23S rRNA V domain in vitro. The mean pyretolytic time for the fluoroquinolone group was 4.7 ±2.9 d, which was significantly shorter than 8.2 ±4.1 d for the azithromycin group. Conclusions: Macrolides are not the first-line treatment for M. pneumoniae respiratory tract infections in Yantai.

Resumen Introducción: Neumonía adquirida por en la comunidad (NAC) es una enfermedad responsable por un gran número de muertes y un impacto económico importante. Debido a que el diagnostico incrementó la sensibilidad, se cambió la etiología de la NAC. Adicionalmente, Mycoplasma pneumoniae es uno de los patógenos que causan la NAC. Los macrólidos y antibióticos relacionados son la primera línea de tratamiento para M. pneumoniae. La resistencia a macrólidos se aumentó en los últimos 15 años y ahora se encuentra distribuido en todo el mundo. Nosotros realizamos el primer estudio de resitencia a M. pneumoniae a los macrólidos en Yantai. Esto podría ser útil para determinar una terapia apropiada para NAC en esta población. Objetivo: Investigar la tasa y el mecanismo para la resitencia a los macrólidos en Yantai. Métodos: Se colectaron muestras faringeas usando un hisopo. Las muestras se analizaron mediante la reacción en cadena de la polimerasa (PCR) y por cultivo para M. pneumoniae. Se uso una PCR anidad para amplificar fragmentos del gen 23S rRNA especifico con las mutaciones para M. pneumoniae. Se analizaron amplicomes por CE-SSCP para determinar la resitencia a los macrólidos. Estos resultados se confirmaron por secuenciación. Se aislaron 27 cepas de M. pneumoniae y se probaron nueve antibióticos in vitro. Resultados: De 128 muestras, 27 fueron positivas para M. pneumoniae. Se determinó una resistencia a macrólidos por Mycoplasma del 100%. Los mecanismos de esta resitencia fue una mutacion punctual A2063G en la secuencia que se une directamente a los macrólidos en el dominio 23S rRNA V in vitro. El tiempo piotolítico medio para el grupo de fluoroquinolonas fue 4.7 ±2.9 d, que fue significativamente más corto que para el grupo de azitromicina: 8.2 ±4.1 d. Conclusiones: Los macrólidos no son la primera linea de tratamiento para las infecciones del tracto respiratorio contra M. pneumoniae respiratory tract infections en Yantai.

Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGF­ß1, TNF­α and NF­κB.

Pulmonary fibrosis is a chronic, progressive, lethal lung disease characterized by alveolar cell necrosis and dysplasia of interstitial fibrotic tissue, resulting in loss of lung function and eventual respiratory failure. Previously, glucocorticoid drugs were used to treat this lung disorder. However, positive responses were recorded in less than half of treated patients and the cytotoxicity caused by high dosage treatment is still a concern. The present study investigated whether ulinastatin, a typical urinary trypsin inhibitor that mitigates numerous inflammatory responses, could be a treatment option for lung fibrosis. The results demonstrated that ulinastatin had the ability to ameliorate interstitial fibrosis and alveolar exudates and to protect against lung diseases induced by smoke, irradiation or silica particles. The mechanism of ulinastatin resulted in the downregulation of inflammatory cascades: Transforming growth factor­ß1, tumor necrosis factor­α and nuclear factor­κB, as demonstrated by western blotting and ELISA. Ulinastatin treatment with a high dose (100,000 U/kg body weight/day) resulted in an attenuated inflammatory response, and inhibited fibrosis formation in lungs, suggesting that ulinastatin may become a part of a clinical therapeutic strategy.

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro.

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ­rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ­rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ­rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ­ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.

Gamma-synuclein binds to AKT and promotes cancer cell survival and proliferation.

Hyperactivation of AKT plays a critical role in the survival and proliferation of cancer cells. However, the molecular mechanisms underlying AKT activation remain elusive. Here, we tested the effect of γ-synuclein, a member of the synuclein family of proteins, on the activation of AKT. We show that the expression level of γ-synuclein is increased in non-small cell lung cancer (NSCLC) tissues. γ-Synuclein binds to the protein kinase domain of AKT and promotes its phosphorylation. Overexpression of γ-synuclein in H157 cells enhances cell proliferation and protects the cells from staurosporine-induced cytotoxicity. Knockdown of γ-synuclein attenuates AKT activation and cell proliferation induced by epidermal growth factor. The effect of γ-synuclein is abolished when AKT is depleted. Thus, γ-synuclein promotes cell survival and proliferation via activating AKT and may play a causal role in the pathogenesis of NSCLC.

Cullin7 is required for lung cancer cell proliferation and is overexpressed in lung cancer.

Ubiquitin ligase Cullin7 has been identified as an oncogene in some malignant diseases such as choriocarcinoma and neuroblastoma. However, the role of Cullin7 in lung cancer carcinogenesis remains unclear. In this study, we explored the functional role of Cullin7 in lung cancer cell proliferation and tumorigenesis and determined its expression profile in lung cancer. Knocking down Cullin7 expression by small interfering RNA (siRNA) in lung cancer cells inhibited cell proliferation and elevated the expression of p53, p27, and p21 proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. Cullin7 knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, Cullin7 expression was increased in primary lung cancer tissues of humans. Thus, Cullin7 is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of lung cancer. Thus, our study provided evidence that Cullin7 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer management.

STK33 overexpression in hypopharyngeal squamous cell carcinoma: possible role in tumorigenesis.

BACKGROUND: The role of serine/threonine kinase 33 (STK33) gene in tumorigenesis is still controversial. This study was aimed to investigate whether STK33 had the effect on hypopharyngeal squamous cell carcinoma (HSCC) and relevant genes, as well as the potential relation to ERK1/2 pathway. METHODS: Immunohistochemistry was performed to investigate STK33 expression in human HSCC specimens. MTT, immunofluorescence, clone formation and matrigel invasion assays were employed to detect the effects of STK33 knockdown (STK33-RNAi) and/or PD98059 on major oncogenic properties of a HSCC cell line (Fadu), while, real-time PCR and western blot were used to examine the expressions of relevant genes. RESULTS: STK33 was over-expressed in HSCC specimens, which was significantly associated with certain clinicopathological parameters. STK33-RNAi in Fadu cells resulted in inhibition of proliferation, induction of apoptosis, reduction of clone formation, and decline in the migration and invasion. These effects were potentiated by administration of PD98059. Mechanistic studies revealed that STK33-RNAi led to an increase in Caspse-3, Nm-23-H1 and E-Cadherin expressions and a reduction in Bcl-2, Ki-67 and Vimentin expressions. Moreover, PD98059 significantly reduced both ERK1/2 and STK33 expressions in Fadu cells. CONCLUSIONS: STK33 is a potential oncogene and a promising diagnostic marker for HSCC. STK33 may promote tumorigenesis and progression of HSCC, and serve as a valuable molecular target for treatment of HSCC.

Bronchial anatomy of left lung: a study of multi-detector row CT.

Familiarity with prevailing pattern and variations in the bronchial tree is not only essential for the anatomist to explain bronchial variation in bronchial specimens, but also useful for guiding bronchoscopy and instructing pulmonary segmental resection. The purpose of this study was designed to demonstrate various branching patterns of left lung with 3D images, with special attention given to identify the major types at transverse thin-section CT. Two hundred and sixteen patients with routine thorax scans were enrolled. The images of bronchial tree, virtual bronchoscopy were reconstructed using post-processing technique of multi-detector row CT. We attempted to classify the segmental bronchi by interpreting the post-processing images, and identified them in transverse thin-section CT. Our results showed that the segmental bronchial ramifications of the left superior lobe were classified into three types mainly, i.e., common stem of apical and posterior segmental bronchi (64%, 138/216); trifurcation (23%, 50/216); common stem of apical and anterior segmental bronchi (10%, 22/216), and they could be identified at two typical sections of transverse thin-section CT. There were two major types in left basal segmental bronchi, i.e., bifurcation (75%, 163/216), trifurcation (18%, 39/216), and they could also be identified at two typical sections of transverse thin-section CT. In conclusion, our study have offered simplified branching patterns of bronchi and demonstrated various unusual bronchial branching patterns perfectly with 3D images, and have also revealed how to identify the main branching patterns in transverse thin-section CT.

Coxsackievirus B3 affects endothelial tight junctions: possible relationship to ZO-1 and F-actin, as well as p38 MAPK activity.

Tight junction (TJ) plays a pivotal role in preventing the invasion of pathogens from the blood to extracellular environment. However, the mechanisms by which Group B coxsackievirus 3 (CVB(3)) can get through TJ from the apical surface still remain obscure. In the present study, the human umbilical vein endothelial cell (HUVEC) was utilized to investigate the alterations in F-actin and ZO-1 status, permeability as well as p38 mitogen-activated protein kinase (MAPK) activity in response to CVB(3) by means of fluorescence labeling, flow cytometry, and macromolecule permeability assay. We found that CVB(3) was able to induce reorganization of F-actin and redistribution of ZO-1, increase the level of F-actin, and elevate the permeability of FITC-albumin. Moreover, CVB(3)-mediated the above effects involve in P38 MAPK activation. Our preliminary study indicates that CVB(3)-induced alteration in permeability may be attributed to disruption of F-actin and ZO-1 organizations and that SB203580, a specific P38 MAPK inhibitor, can reverse these effects. The precise mechanisms underlying the CVB(3)-mediated effects on HUVECs need to be studied further.